The associations of age-related macular degeneration (AMD) with cataracts, prior cataract surgery, cumulative exposure to sunlight and pigmentation and new understanding of how A2E is created and detoxified within the retinal pigment epithelium (RPE) support the hypothesis that chronic photochemical injury drives macular changes with age and early AMD progression. Lipofuscin accumulates with age in the RPE and co-localizes with acute photosensitization of reactive oxygen intermediates (ROI) in the primate retina. We model the normal accumulation of potentially damaging photoproducts with age in the RPE and Bruchs Membrane (BM) complex as well as changes induced by additional spectral filtering of light reaching the macula. Lipofuscin granules contain at least 10 different fluorescent photochemical products including A2E (N-retinylidene-N-retinylethanolamine), its epoxides and other as yet chemically unidentified A2E-related fluorophores. The precursors (A2PE and A2PEH2) of these fluorophores originate from reactions of all-trans-retinal within the receptor outer segments (ROS) during periods associated with significant rhodopsin bleaching (i.e., normal daylight). Although RPE lysosomal processing enzymatically digests over 99% of the shed ROS contents, A2E and related fluorophores are not digested, but are concentrated into lipofuscin granules. By age 60 years, the average concentration of A2E within RPE cells reaches 400 micromolar in normal eyes. However, A2E is toxic to cellular membranes at much lower concentrations. We hypothesize that segregation of A2E into lipofuscin granules and prevention of its redistribution into critical membranes is required for RPE health. We developed a biophysical model using normal values of pupil size, lens transmission, and rod dark adaptation time constant (trh) to determine average retinal spectral irradiance, steady-state concentration of all-trans-retinal, all-trans-retinal photosensitization of oxidative damage, all-trans-retinal reactions to form A2E-related species in the ROS, and A2E photo-oxidation within RPE lipofuscin granules as a function of age and ambient light intensity. Our model predicts a decline of about one third in the action spectra-weighted short-wavelength macular irradiance with each decade and a nearly constant production rate of A2E-related fluorophores in the RPE during the first 60 years (falling significantly thereafter). A similar age dependence of total lipofuscin granule volume and total fluorescence per RPE cell was reported recently in human cadaver eyes. Since the rates of lipofuscin increase with age are slower than the rate of decrease in short-wavelength macular irradiance in the phakic eye with age, ROI photosensitization in the RPE should also fall with increasing age. Photo-oxidative stress in the outer retina might arise from the smaller amounts of A2E-related fluorophores observed in critical membranes of the RPE/BM complex. However, if the RPE/BM complex were the site of photo-oxidative injury driving AMD progression, the magnitude and rate of this oxidative injury would be expected to increase dramatically (not observed) following cataract removal and intraocular lens (IOL) implantation. Consequently, we propose a novel hypothesis that singlet oxygen generation by RPE lipofuscin allows the chemical alteration of accumulating A2E, thereby limiting the steady-state levels of A2E (A2Ess) in the RPE, the redistribution of A2E into retinal membranes, and associated A2E chemical toxicity. Singlet oxygen generated photochemically within the lipofuscin granule reacts with its A2E to form A2E epoxides which then react to form increasingly complex cross-linked molecules. As short-wavelength macular irradiance falls with age, the rate of A2E photo-oxidation falls approximately up to 20-fold, causing A2Ess in the normal phakic eye to increase even as rod bleaching and A2E production decrease. Our theoretical model of macular aging reproduces the normal age dependence of lipofuscin and A2E and provides a primary cytotoxic mechanism in which, once A2E exceeds a cytotoxic threshold concentration in the RPE cell, A2E redistribution into critical membranes causes damage and loss of RPE function with or without additional photo-activation. In our model, it is primarily the yellowing of the lens with age that distorts the original spectral balance between rate of production and rate of photo-oxidation found in youth, and allows the A2Ess to rise with age. We are evaluating noninvasive retinal imaging methods that might permit clinical validation of our predictions of photochemical changes following cataract surgery and our predictions of the benefits of specific spectral photo-protective filters. We have designed and had manufactured bicolored sunglasses with two different specific spectrally selective lenses that provide equivalent spectral photoactivation of lipofuscin photosensitization of singlet oxygen but very different degrees of rod activation in bright ambient light. Our model predicts that in young eyes or elderly pseudophakes the levels of A2PEH2 production in the rods and the A2Ess levels in the RPE will be remarkably divergent between left and right eyes in individuals wearing these sunglasses over a period of a few months of significant outdoor daylight activity. In order to distinguish the steady-state levels of different RPE photoproducts in the retina noninvasively, we are developing spectral imaging capabilities by modifying confocal scanning laser ophthalmoscopes and fundus cameras. We are currently evaluating the potential of these modified clinical instruments for noninvasive monitoring of the molecular effects of such filters in patients. Furthermore, we expect that improved spectral separation of the different species in the A2E pathway along with high resolution noninvasive imaging of the human retina, should enable us to quantify early microscopic abnormalities that we believe are the earliest stages in age-related maculopathy leading to AMD as well as genetically -linked diseases such as Stargardts macular dystrophy. Such quantitative early intermediate endpoints may prove critical in developing new more efficient clinical studies of AMD prevention. In collaboration with the NEI,the Eye Institute of the Russian Academy of Medicine, National Naval Medical Center and Walter Reed Army Medical Center, we are designing clinical studies of the effects of such filters on progression of both early and moderate AMD following cataract surgery and IOL implantation and macular changes in subjects with genetic predisposition to generation of increased A2E and lipofuscin at younger ages. We have recently begun a retrospective analysis of the observed asymmetries between left and right in lens status and in AMD progression in the AREDS1 database. We have extended our biophysical model to the effects of spectral irradiance changes on the activation by blue light of melanopsin uniquely found in the membranes of the small subpopulation of retinal ganglion cells which entrain circadian processes, control steady-state pupil size and affect attention via their projections to the brain. In this work we are focusing on how to optimize the daily variations in retinal spectral irradiance by programmable ambient light sources and ocular filters for better health. Research suggests that both lens yellowing with age and the widespread use of blue-rich artificial lighting at night may increase circadian and attention disorders in modern life. We are developing temporally and spectrally programmable light sources and testbeds to develop better understanding of their effects on this neural pathway and to create optimized artificial lighting environments for human health and productivity.